BDNF Val66Met genotype and adolescent glucocorticoid treatment induce sex-specific disruptions to fear extinction and amygdala GABAergic interneuron expression in mice.

BACKGROUND: The BDNF Val66Met single nucleotide polymorphism has been implicated in stress sensitivity and Post-Traumatic Stress Disorder (PTSD) risk. We previously reported that chronic young-adult stress hormone treatment enhanced fear memory in adult BDNFVal66Met mice with the Met/Met genotype. This study aimed to extend this work to fear extinction learning, spontaneous recovery of fear, and neurobiological correlates in the amygdala. METHODS: Male and female Val/Val and Met/Met mice received corticosterone in their drinking water during late adolescence to model chronic stress. Following a 2-week recovery period, the mice underwent fear conditioning and extinction training. Immunofluorescent labelling was used to assess density of three interneuron subtypes; somatostatin, parvalbumin and calretinin, within distinct amygdala nuclei. RESULTS: No significant effects of genotype, treatment or sex were found for fear learning. However, adolescent CORT treatment selectively abolished fear extinction of female Met/Met mice. No effect of genotype, sex, or treatment was observed for spontaneous recovery of fear. Significant main effects of genotype and CORT emerged for somatostatin and calretinin cell density, again in females only, further supporting sex-specific effects of the Met/Met genotype and chronic CORT exposure. CONCLUSION: BDNF Val66Met genotype interacts with chronic adolescent stress hormone exposure to abolish fear extinction in female Met/Met mice in adulthood. This effect was associated with female-specific interneuron dysfunction induced by either genotype or stress hormone exposure, depending on the interneuron subtype. These data provide biological insight into the role of BDNF in sex differences in sensitivity to stress and vulnerability to stress-related disorders in adulthood.

Can virtual learning environments be used as research platforms?

BACKGROUND: Many higher education institutions use virtual learning environments (VLEs), with one in seven students learning exclusively online. The use of online research methods and approaches has also gained momentum over the past decade. AIM: To explore the use of VLEs for qualitative research. DISCUSSION: Using VLEs for purposes beyond teaching and learning functions offers various opportunities, providing a method of collecting data that has minimal costs, requires few resources, offers maximum flexibility, has apt technical support and engages participants. However, it also has several challenges. CONCLUSION: This study supports the proposed potential value and appropriateness of using VLEs to collect data. The function of VLEs may be significantly widened at reasonable cost and challenge. Work in this regard is encouraged. IMPLICATION FOR PRACTICE: VLEs may be used in nurse education research, which stands to benefit from this opportunity at reasonable cost and challenge.

Brain-Derived Neurotrophic Factor Val66Met polymorphism interacts with adolescent stress to alter hippocampal interneuron density and dendritic morphology in mice.

Brain-derived neurotrophic factor (BDNF) plays essential roles in GABAergic interneuron development. The common BDNF val66met polymorphism, leads to decreased activity-dependent release of BDNF. The current study used a humanized mouse model of the BDNF val66met polymorphism to determine how reduced activity-dependent release of BDNF, both on its own, and in combination with chronic adolescent stress hormone, impact hippocampal GABAergic interneuron cell density and dendrite morphology. Male and female Val/Val and Met/Met mice were exposed to corticosterone (CORT) or placebo in their drinking water from weeks 6-8, before brains were perfuse-fixed at 15 weeks. Cell density and dendrite morphology of immunofluorescent labelled inhibitory interneurons; somatostatin, parvalbumin and calretinin in the CA1, and 3 and dentate gyrus (DG) across the dorsal (DHP) and ventral hippocampus (VHP) were assessed by confocal z-stack imaging, and IMARIS dendritic mapping software. Mice with the Met/Met genotype showed significantly lower somatostatin cell density compared to Val/Val controls in the DHP, and altered somatostatin interneuron dendrite morphology including branch depth, and spine density. Parvalbumin-positive interneurons were unchanged between genotype groups, however BDNF val66met genotype influenced the dendritic volume, branch level and spine density of parvalbumin interneurons differentially across hippocampal subregions. Contrary to this, no such effects were observed for calretinin-positive interneurons. Adolescent exposure to CORT treatment also significantly altered somatostatin and parvalbumin dendrite branch level and the combined effect of Met/Met genotype and CORT treatment significantly reduced somatostatin and parvalbumin dendrite spine density. In sum, the BDNFVal66Met polymorphism significantly alters somatostatin and parvalbumin-positive interneuron cell development and dendrite morphology. Additionally, we also report a compounding effect of the Met/Met genotype and chronic adolescent CORT treatment on dendrite spine density, indicating that adolescence is a sensitive period of risk for Val66Met polymorphism carriers.

Sex-specific spatial memory deficits in mice with a conditional TrkB deletion on parvalbumin interneurons.

Schizophrenia is a debilitating disorder characterised by three main symptom categories: positive, negative and cognitive. Cognitive symptoms emerge first, and currently do not have appropriate treatments, despite being a strong predictor of the severity and progress of the illness. Cognitive deficits are strongly associated with the dysfunction of GABAergic parvalbumin interneurons (PV-IN). PV-IN are supported by Brain-Derived Neurotrophic Factor (BDNF) via its receptor Tropomyosin-related Kinase B (TrkB). The main aim of this study was to investigate the cognitive and affective consequences of disrupted BDNF-TrkB signalling at PV-IN. We crossed PV-Cre mice with heterozygous TrkB floxed mice (PV-Cre:Fl+/-) to knock-down TrkB receptors on PV-IN. Male and female mice underwent a battery of tests including: Y-Maze, Cheeseboard Maze, Elevated Plus Maze, and Locomotor activity. Co-expression of PV and TrkB in the hippocampus was assessed by fluorescent immunohistochemistry and detailed stereology. Sex-specific spatial memory impairments were found in the Y-Maze. Only male PV-Cre:Fl+/- mice showed no preference for the novel arm. Furthermore, there was a male specific genotype difference in memory retrieval in the Cheeseboard Maze. Male PV-Cre:Fl+/- mice were more preservative in their learning than male PV-Cre control mice. Overall, the evidence from this study suggests that sex had a developmental influence on this constitutive model. Male spatial memory was altered by the disruption to BDNF-TrkB signalling at PV-IN. This aligns with males showing more severe cognitive dysfunction in schizophrenia.

Sex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental "Two-Hit" Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation.

Neurodevelopmental disorders are thought to be caused by a combination of adverse genetic and environmental insults. The "two-hit" hypothesis suggests that an early first "hit" primes the developing brain to be vulnerable to a second "hit" during adolescence which triggers behavioral dysfunction. We have previously modeled this scenario in mice and found that the combined effect of a genetic hapolinsuffuciency in the brain-derived neurotrophic factor (BDNF) gene (1st hit) and chronic corticosterone (CORT) treatment during adolescence (2nd hit), caused spatial memory impairments in adulthood. Environmental enrichment (EE) protocols are designed to stimulate experience-dependent plasticity and have shown therapeutic actions. This study investigated whether EE can reverse these spatial memory impairments. Wild-type (WT) and BDNF heterozygous (HET) mice were treated with corticosterone (CORT) in their drinking water (50 mg/L) from weeks 6 to 8 and exposed to EE from 7 to 9 weeks. Enriched housing included open top cages with additional toys, tunnels, housing, and platforms. Y-maze novel preference testing, to assess short-term spatial memory, was performed at 10 weeks of age. At week 16 dorsal hippocampus tissue was obtained for Western blot analysis of expression levels of BDNF, the BDNF receptor TrkB, and NMDA receptor subunits, GluNR1, 2A and 2B. As in our previous studies, spatial memory was impaired in our two-hit (BDNF HET + CORT) mice. Simultaneous EE prevented these impairments. However, EE appeared to worsen spatial memory performance in WT mice, particularly those exposed to CORT. While BDNF levels were lower in BDNF HET mice as expected, there were no further effects of CORT or EE in males but a close to significant female CORT × EE × genotype interaction which qualitatively corresponded with Y-maze performance. However, EE caused both sex- and genotype-specific effects on phosphorylated TrkB residues and GluNR expression within the dorsal hippocampus, with GluNR2B levels in males changing in parallel with spatial memory performance. In conclusion, beneficial effects of EE on spatial memory emerge only following two developmental disruptions. The mechanisms by which EE exerts its effects are likely via regulation of multiple activity-dependent pathways, including TrkB and NMDA receptor signaling.